Hepatocyte Growth factor/scattering factor (HGF/SF) is a pleiotropic cytokine that performs various functions in developmental processes. HGF/SF binds to its receptor Met tyrosine kinase to induce various bioreactions, including the migration, invasion, proliferation, survival and morphological change of target cells (Jiang et al., Critical Reviews in Oncology/Hematology. 53:35-69, 2005). HGF/SF is a cytokine of mesenchymal origin and was reported to act on hepatocytes and other epithelial cells, including endothelial cells, melanocytes, hematopoietic cells and osteocytes, to activate the above reactions through its receptor Met (Tamagnone and Comoglio, Cytokine & Growth factor Rev. 8:129-142, 1997).
The present inventors previously reported that the deregulation of HGF/SF-Met signaling does not influence the usual function of hepatocytes, but adversely affects the regeneration of damaged hepatocytes. Since then, the present inventors confirmed that, when the skin in addition to the liver is damaged, HGF/SF and c-Met are secreted. In other words, large amounts of HGF/SF and c-Met are secreted from hyperproliferative skin tissue to promote the proliferation of skin cells. However, it was reported that c-Met is found in the skin and hair follicles, whereas HGF/SF is usually expressed only in hair follicles and is found in damaged skin. Thus, HGF/SF remains in an inactivated state until the skin is damaged, and it is activated around wounds after the skin is damaged (Journal of Cell Biology 177(1):151-162, 2007). Accordingly, it is known that HGF/c-Met directly regulate skin regeneration and repair (Nakamura et al., Nature. 342:440-443, 1993; Huh et al., Proc Natl Acad Sci USA. 101:4477-4482, 2004).
In vivo and laboratory studies indicated that HGF/SF also acts on the nervous system, and many studies on the function of HGF/SF to protect motor neurons were reported (Novak et al., Journal of Neuroscience. 20:326-337, 2000). In addition, it was suggested that HGF/SF plays an important role in defensive physiological mechanisms following general organ damage such as heart damage (Nakamura et al., J Clin Invest. 106:1511-1519, 2000). Indeed, it was demonstrated that the HGF/MET pathway is involved in the processes of cardiac infraction, progressive nephritis, liver cirrhosis and pulmonary fibrosis and that HGF is overexpressed in lesions of such degenerative diseases to exhibit a physiological activity of protecting tissue from damage (Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008).
Therefore, it has been suggested that HGF/SF can be developed as an agent for preventing the death of neural cells in the central nervous system, and an agent for treating neurodegenerative diseases, including Parkinson's disease, ischemia leading to nervous infarction, and also regenerative therapeutic agents that are used after the occurrence of damage to the heart, the kidneys, the liver and the lungs, as well as ulcerative wounds.
The excessive activity of HGF/c-Met signaling is associated with tumorigenesis of various endothelial cells and angiogenesis, and from this point of view, it was suggested that an antagonistic c-Met antibody that targets c-Met can be used as an anticancer agent (Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008). For example, it was reported that a one-armed c-Met antibody efficiently inhibits tumor growth in a transplanted mouse model by negatively regulating the activation of HGF caused by dimerization of c-Met (Jin et al, Cancer Research 68(11): 4360-4368, 2008; Comoglio et al., Nature Review Drug Discovery. 7:504-516, 2008). In addition, in T-cell therapy, an antibody to an antigen that is overexpressed in cancer cells is used in tumor targeting for linking of T cells in the genetic manipulation of T cells that selectively recognizes a cancer cell surface antigen (Sadelain, The Cancer Journal 15(6):451-455, 2009).